Cancer Management and Research (2019-04-01)

Evaluating venetoclax and its potential in treatment-naïve acute myeloid leukemia

  • Knight T,
  • Edwards H,
  • Taub JW,
  • Ge Y

Journal volume & issue
Vol. Volume 11
pp. 3197 – 3213

Abstract

Read online

Tristan Knight,1,2 Holly Edwards,3,4 Jeffrey W Taub,1–2,4 Yubin Ge2–41Division of Pediatric Hematology and Oncology, Department of Pediatrics, Children’s Hospital of Michigan, Detroit, MI, USA; 2Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA; 3Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; 4Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USAAbstract: Venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was recently approved by the US Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (AML) in adult patients aged 75 years or older, or otherwise unable to tolerate intensive induction chemotherapy, in combination with either hypomethylating agents or low-dose cytarabine. In this review article, we discuss venetoclax’s mechanism of action, in relation to both the BCL-2 protein family in general and BH3-mimetic activity in particular. We then outline the pharmacological advances that preceded and facilitated its development, as well as providing an overview of key preclinical and clinical studies which lead to its use first in chronic lymphoid leukemia (CLL), then in small lymphocytic leukemia (SLL), and subsequently in AML. Finally, we seek to offer an overview of the challenges and opportunities encountered as venetoclax moves into more widespread use, including its use and activity against leukemia initiating cells and oxidative phosphorylation.Keywords: ABT-199, acute myeloid leukemia, apoptosis, BCL-2 inhibitor, BH3-mimetic, venetoclax

Keywords